Neuromechanical basis of baroreceptor function

压力感受器功能的神经力学基础

• 批准号: 7851330
• 负责人: JOHN H SCHILD
• 金额: $ 42.03万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851330
• 关键词: Accounting; Acute; Age; Aging; Anatomy; Aorta; Arteries; Atherosclerosis; Automobile Driving; Baroreflex; Basement membrane; Biomedical Engineering; Blood Pressure; Blood Vessels; Brain; Cardiovascular Pathology; Cardiovascular Physiology; Cellular Mechanotransduction; Chronic; Clinical; Code; Collagen; Collagen Fiber; Companions; Complement; Complex; Computer Simulation; Computers; Computing Methodologies; Data; Disease; Elastin; Electron Microscopy; Electrons; Event; Face; Fiber; Free Nerve Ending; Functional disorder; Health; Heart; Heart Rate; Hypertension; Impairment; In Vitro; Ion Channel; Label; Lead; Measurement; Mechanics; Mechanoreceptors; Mediating; Membrane; Methodology; Microanatomy; Microscopic; Microscopy; Modification; Molecular; Nerve Endings; Neuroanatomy; Neuromechanics; Neurons; Oxidative Stress; Pathology; Physicians; Physiological; Positioning Attribute; Pressoreceptors; Process; Property; Rattus; Regional Anatomy; Relative (related person); Research; Resolution; Risk; Stretching; Structure-Activity Relationship; Subgroup; Syncope; Testing; Time; Tissues; Work; age related; autocrine; autonomic reflex; base; cholinergic; clinically relevant; clinically significant; computer studies; conditioning; density; extracellular; heart function; hemodynamics; immunoreactivity; insight; neuromechanism; neuronal cell body; neuroregulation; paracrine; pressure; protein expression; public health relevance; relating to nervous system; response; sensor; spatial integration; sudden cardiac death; vector

DESCRIPTION (provided by applicant): Arterial baroreceptors (BR) are essential for reliable neural control of heart rate and blood pressure. The data quantifying the properties of these pressoreceptors and the reflexogenic consequences of BR function and dysfunction are extensive. Experimental interpretations of baroreflex dysfunction and cardiovascular pathologies such as neurally mediated syncope, dysrhythmias and hypertension are of significant clinical importance. Age related changes in arterial wall properties strongly correlate with cardiovagal baroreflex impairment, increased levels of blood pressure variability, an impaired ability to respond to acute hemodynamic challenges and increased risk of sudden cardiac death (Monahan, 2007). The BR sensor itself represents an essential functional intersection across these diverse pathologies and yet a clarifying explanation of the transduction machinery is lacking. Our working hypothesis is that the microanatomy, extracellular tissue matrix, excitable neural membrane of the BR terminal complex and regional arterial wall tissues all make functionally distinct contributions to the spatial integration and transduction of localized micromechanical forces arising from arterial pressure dynamics. Our specific aims center upon the neuromechanical properties of myelinated and unmyelinated rat aortic BR as these are accessible for both micro- and macroscopic study using three complementary methodologies: 1) confocal, electron and fluorescent microscopy in conjunction with immunohistochemical labeling of protein expression within, and the tissue constructs that circumscribe, the BR terminal ending, 2) extracellular recording of aortic BR fiber discharge in response to computer controlled pressure loading of the arterial wall and 3) synthesis of these disparate microscopy and biophysical data into comprehensive computational models of the neural and micromechanical mechanisms of mechanosensory transduction that are inaccessible for direct testing and measurement. Our preliminary results illustrate: 1) essential differences between the topological distribution of molecularly identified ion channels along the ultrastructure of BR terminals with myelinated and unmyelinated fibers, 2) a minimum complement of the ion channels expressed at the cell body of BR neurons may underlie the neurogenic mechanisms of mechanotransduction and 3) that these ionic mechanisms contribute to, but cannot entirely account for, such dynamic properties as adaptation, hysteresis and resetting of discharge threshold. This combined experimental and computational strategy is producing a more biophysical understanding of the structure-function relationships associated with BR afferents relative to the basement membrane about the terminal ending, the elastin and collagen fibers within the surrounding tissue matrix as well as the neuro-integrative processes of mechanotransduction. As we recently demonstrated (Feng et al., 2007), this integrative approach can lead to new insights concerning acute cardiovascular pathologies that are well known to invoke autonomic reflexes through activation of arterial mechanoreceptors. PUBLIC HEALTH RELEVANCE: In order for the brain to properly control the heart it must continually receive information concerning blood pressure and heart rate. This application involves experimental bioengineering research related to the arterial pressure sensors (baroreceptors) that provide this critically important information to the brain. A more detailed understanding of how these sensors normally work and adapt to short and long term changes in blood pressure, heart rate and the condition of the arteries (e.g. with aging) will help physicians better manage heart function under conditions of health and disease.

描述（由申请人提供）：动脉压力感受器（BR）对于心率和血压的可靠神经控制至关重要。量化这些压力感受器的性质和BR功能和功能障碍的反射性后果的数据是广泛的。压力感受性反射功能障碍和心血管疾病如神经介导的晕厥、心律失常和高血压的实验解释具有重要的临床意义。动脉壁特性的年龄相关变化与心迷走神经压力感受器反射受损、血压变异性水平升高、对急性血流动力学挑战的反应能力受损和心源性猝死风险升高密切相关（Monahan，2007）。BR传感器本身代表了这些不同病理的基本功能交叉点，但缺乏对转导机制的澄清解释。我们的工作假设是，显微解剖结构，细胞外组织基质，BR终端复杂的可兴奋的神经膜和区域动脉壁组织都作出功能不同的贡献，局部微机械力的空间整合和转导所产生的动脉压力动态。我们的具体目标集中在有髓鞘和无髓鞘大鼠主动脉BR的神经力学特性上，因为这些特性可用于使用三种互补方法的微观和宏观研究：1）共聚焦、电子和荧光显微术结合免疫组织化学标记BR末端内的蛋白表达以及限制BR末端的组织构建体，2）响应于计算机控制的动脉壁压力负荷的主动脉BR纤维放电的细胞外记录，以及3）将这些不同的显微镜和生物物理数据合成为机械感觉转导的神经和微机械机制的综合计算模型，这些模型是直接不可访问的。测试和测量。我们的初步结果说明：1）分子鉴定的离子通道沿着具有有髓和无髓纤维的BR末端的超微结构的拓扑分布之间的本质差异，2）在BR神经元的细胞体处表达的离子通道的最小补充可能是机械转导的神经原性机制的基础，以及3）这些离子机制有助于，但不能完全解释，放电阈值的自适应、滞后和重置等动态特性。这种结合实验和计算的策略产生更多的生物物理的理解与BR传入相对于基底膜的末端，周围组织基质内的弹性蛋白和胶原纤维，以及机械转导的神经整合过程的结构-功能关系。正如我们最近所证明的（Feng et al.，2007），这种综合方法可以导致关于急性心血管病理学的新见解，所述急性心血管病理学众所周知通过激活动脉机械感受器来引起自主反射。公共卫生相关性：为了使大脑正确地控制心脏，它必须不断地接收有关血压和心率的信息。该应用涉及与动脉压力传感器（压力感受器）相关的实验生物工程研究，该传感器为大脑提供这一至关重要的信息。更详细地了解这些传感器如何正常工作并适应血压，心率和动脉状况（例如老化）的短期和长期变化，将有助于医生在健康和疾病条件下更好地管理心脏功能。